Rhiannon Macefield

Developing core outcomes sets: methods for identifying and including patient-reported outcomes (PROs)

BackgroundSynthesis of patient-reported outcome (PRO) data is hindered by the range of available PRO measures (PROMs) composed of multiple scales and single items with differing terminology and content. The use of core outcome sets, an agreed minimum set of outcomes to be measured and reported in all trials of a specific condition, may improve this issue but methods to select core PRO domains from the many available PROMs are lacking. This study examines existing PROMs and describes methods to identify health domains to inform the development of a core outcome set, illustrated with an example.MethodsSystematic literature searches identified validated PROMs from studies evaluating radical treatment for oesophageal cancer. PROM scale/single item names were recorded verbatim and the frequency of similar names/scales documented. PROM contents (scale components/single items) were examined for conceptual meaning by an expert clinician and methodologist and categorised into health domains. A patient advocate independently checked this categorisation.ResultsSearches identified 21 generic and disease-specific PROMs containing 116 scales and 32 single items with 94 different verbatim names. Identical names for scales were repeatedly used (for example, ‘physical function’ in six different measures) and others were similar (overlapping face validity) although component items were not always comparable. Based on methodological, clinical and patient expertise, 606 individual items were categorised into 32 health domains.ConclusionThis study outlines a methodology for identifying candidate PRO domains from existing PROMs to inform a core outcome set to use in clinical trials.

Impact of prostate cancer testing: an evaluation of the emotional consequences of a negative biopsy result

Background:When testing for prostate cancer, as many as 75% of men with a raised prostate-specific antigen (PSA) have a benign biopsy result. Little is known about the psychological effect of this result for these men.Methods:In all, 330 men participating in the prostate testing for cancer and treatment (ProtecT) study were studied; aged 50–69 years with a PSA level of ⩾3 ng ml−1 and a negative biopsy result. Distress and negative mood were measured at four time-points: two during diagnostic testing and two after a negative biopsy result.Results:The majority of men were not greatly affected by testing or a negative biopsy result. The impact on psychological health was highest at the time of the biopsy, with around 20% reporting high distress (33 out of 171) and tense/anxious moods (35 out of 180). Longitudinal analysis on 195 men showed a significant increase in distress at the time of the biopsy compared with levels at the PSA test (difference in Impact of Events Scale (IES) score: 9.47; 95% confidence interval (CI) (6.97, 12.12); P<0.001). These levels remained elevated immediately after the negative biopsy result (difference in score: 7.32; 95% CI (5.51, 9.52); P<0.001) and 12 weeks later (difference in score: 2.42; 95% CI (0.50, 1.15); P=0.009). Psychological mood at the time of PSA testing predicted high levels of distress and anxiety at subsequent time-points.Conclusions:Most men coped well with the testing process, although a minority experienced elevated distress at the time of biopsy and after a negative result. Men should be informed of the risk of distress relating to diagnostic uncertainty before they consent to PSA testing.

Psychological impact of prostate biopsy: physical symptoms, anxiety, and depression.

PURPOSE To investigate the psychological impact of prostate biopsy, including relationships between physical biopsy-related symptoms and anxiety and depression. PATIENTS AND METHODS A prospective cohort of 1,147 men, nested within the Prostate Testing for Cancer and Treatment trial and recommended to receive prostate biopsy, completed questionnaires assessing physical and psychological harms after biopsy in the Prostate Biopsy Effects study. Psychological impact was measured using the Hospital Anxiety and Depression Scale, and scores were compared according to experiences of biopsy-related symptoms at biopsy, and at 7 and 35 days afterward, and in relation to biopsy results. RESULTS A total of 1,144 men (99.7%) returned questionnaires at biopsy, with 1,090 (95.0%) and 1,016 (88.6%) responding at 7 and 35 days postbiopsy. Most men experienced biopsy-related symptoms as no problem or a minor problem, and overall levels of anxiety and depression were low and similar to normative levels. Of men receiving a negative biopsy result (n = 471), anxiety was greater in those experiencing problematic biopsy-related symptoms compared with those experiencing nonproblematic symptoms at 7 days for the following symptoms: pain (P < .001), shivers, (P = .020), hematuria (P < .001), hematochezia (P < .001), and hemoejaculate (P < .001). Anxiety was reduced, although symptoms were not, after 35 days. Overall levels of anxiety were low across all time points except at the 35-day assessment among men who had received a cancer diagnosis. CONCLUSION Problematic postbiopsy symptoms can lead to increased anxiety, distinct from distress related to diagnosis of prostate cancer. Men and doctors need to consider these additional potential harms of biopsy when deciding whether to initiate prostate-specific antigen testing.

Core information set for oesophageal cancer surgery

Surgeons provide patients with information before surgery, although standards of information are lacking and practice varies. The development and use of a ‘core information set’ as baseline information before surgery may improve understanding. A core set is a minimum set of information to use in all consultations before a specific procedure. This study developed a core information set for oesophageal cancer surgery.

Core Outcomes for Colorectal Cancer Surgery: A Consensus Study.

Background Colorectal cancer (CRC) is a major cause of worldwide morbidity and mortality. Surgical treatment is common, and there is a great need to improve the delivery of such care. The gold standard for evaluating surgery is within well-designed randomized controlled trials (RCTs); however, the impact of RCTs is diminished by a lack of coordinated outcome measurement and reporting. A solution to these issues is to develop an agreed standard “core” set of outcomes to be measured in all trials to facilitate cross-study comparisons, meta-analysis, and minimize outcome reporting bias. This study defines a core outcome set for CRC surgery. Methods and Findings The scope of this COS includes clinical effectiveness trials of surgical interventions for colorectal cancer. Excluded were nonsurgical oncological interventions. Potential outcomes of importance to patients and professionals were identified through systematic literature reviews and patient interviews. All outcomes were transcribed verbatim and categorized into domains by two independent researchers. This informed a questionnaire survey that asked stakeholders (patients and professionals) from United Kingdom CRC centers to rate the importance of each domain. Respondents were resurveyed following group feedback (Delphi methods). Outcomes rated as less important were discarded after each survey round according to predefined criteria, and remaining outcomes were considered at three consensus meetings; two involving international professionals and a separate one with patients. A modified nominal group technique was used to gain the final consensus. Data sources identified 1,216 outcomes of CRC surgery that informed a 91 domain questionnaire. First round questionnaires were returned from 63 out of 81 (78%) centers, including 90 professionals, and 97 out of 267 (35%) patients. Second round response rates were high for all stakeholders (>80%). Analysis of responses lead to 45 and 23 outcome domains being retained after the first and second surveys, respectively. Consensus meetings generated agreement on a 12 domain COS. This constituted five perioperative outcome domains (including anastomotic leak), four quality of life outcome domains (including fecal urgency and incontinence), and three oncological outcome domains (including long-term survival). Conclusion This study used robust consensus methodology to develop a core outcome set for use in colorectal cancer surgical trials. It is now necessary to validate the use of this set in research practice.

Integration of clinical and patient‐reported outcomes in surgical oncology

Patient‐reported outcomes (PROs) provide information about the patient perspective and experience of undergoing surgery for cancer, but evidence suggests that they are not used widely to influence practice. This review considers key challenges and opportunities for using PROs effectively in gastrointestinal surgical oncology, drawing on principles learnt from surgical oncology in general.

Do the risk factors of age, family history of prostate cancer or a higher prostate specific antigen level raise anxiety at prostate biopsy?

To date, little is known of the impact knowledge of personal risk factors has on anxiety in men undergoing biopsy tests for prostate cancer. This analysis explores anxiety scores of men at higher risk due to age, family history of prostate cancer and a higher prostate specific antigen (PSA) level when proceeding from PSA test to prostate biopsy. A prospective cohort of 4198 men aged 50-69 years with a PSA result of >3ng/ml was studied, recruited for the Prostate testing for cancer and Treatment study (ProtecT). Anxiety scores at the time of biopsy were lower in older men (p<0.001). No age group showed an increase in anxiety as the men proceeded from PSA testing to biopsy, although older men did not show the same level of decrease in anxiety as younger men (p=0.035). There was no difference in anxiety scores at biopsy between men with or without a family history of prostate cancer (p=0.68), or between those with a raised PSA of 10-<20ng/ml compared to a PSA result of 3-<10ng/ml (p=0.46). Change in scores since the initial PSA test appeared unaffected by family history (p=0.995) or by PSA result (p=0.76). Within the context of a research study, the increased risk of prostate cancer through older age, having a family history of prostate cancer, or having a significantly elevated PSA level appears to have no detrimental effect on mens anxiety level when proceeding to biopsy.

A systematic review of on-site monitoring methods for health-care randomised controlled trials

Background Monitoring the conduct of clinical trials is recommended by International Conference of Harmonisation Good Clinical Practice (ICH GCP) guidelines and is integral to trial quality assurance. On-site monitoring, that is, visiting trial sites, is one part of this process but little is known about the procedures that are performed in practice. Purpose To examine and summarise published on-site monitoring methods for health-care clinical trials, including evaluations of their benefits and costs to trials. Methods A systematic literature review identified all articles reporting the methods and practices of on-site monitoring of randomised controlled trials (RCTs). Articles were categorised into (1) reports from research groups and organisations, (2) reports from individual RCTs, (3) randomised trials of on-site monitoring interventions, (4) cost simulations, or (5) surveys of trial staff and monitors. Data were extracted on the characteristics of the trials and groups reporting on-site monitoring (e.g., geographical origin, sponsor, and trial focus). Information from articles in categories (1)–(3) was summarised on the frequency and scope of site monitoring visits, monitoring team size and composition, activities during site visits, and reporting structures. Evaluations of the benefits and disadvantages of on-site monitoring were examined for all included articles. Results In total, 57 articles were identified, comprising 21 articles about the on-site monitoring practices of 16 research groups, 30 articles from 26 RCTs, 1 on-site monitoring intervention RCT, 2 cost simulations, and 3 surveys. Publications in categories (1)–(3), mostly originated from the United States (33/52, 63%) or Europe (15/52, 29%), were predominantly describing non-commercial organisations or trials (45/52, 87%), with heart disease (9/26, 35%) or cancer (5/26, 19%) the commonest focus of individual RCTs. The frequency of visits ranged from every 6–8 weeks up to once every 3 years, with mostly all trial sites visited. The number of monitors visiting a site varied between 1 and 8. The most common on-site monitoring activity was verifying source data and consent forms, with a focus on data accuracy. Only six articles evaluated their on-site monitoring process, with improvements observed in recruitment rates and protocol adherence but with direct costs and staff time viewed as the major disadvantages. The on-site monitoring RCT ended prematurely so preventing full assessment. Limitations Trialists and organisations may utilise additional unpublished on-site monitoring systems. The varied terminology used to describe monitoring may have limited identification of some relevant articles. Conclusions This review demonstrated that on-site monitoring is utilised in trials worldwide but systems vary considerably with little evidence to support practice. These on-site monitoring practices need to be evaluated empirically, including costs, to provide robust evidence for the contribution of site visits to trial performance and quality.

Selecting and measuring optimal outcomes for randomised controlled trials in surgery

BackgroundRandomised controlled trials (RCTs) in surgery are complex to design and conduct and face unique challenges compared to trials in other specialties. The appropriate selection, measurement and reporting of outcomes are one aspect that requires attention. Outcomes in surgical RCTs are often ill-defined, inconsistent and at high risk of bias in their assessment and historically, there has been an undue focus on short-term outcomes and adverse events meaning the value of trial results for clinical practice and decision-making is limited.PurposeThis review addresses three key problems with surgical trial outcomes—choosing the right outcomes for the trial design and purpose, selecting relevant outcomes to measure from the range of possible outcomes, and measuring outcomes with minimal risk of bias. Each obstacle is discussed in turn, highlighting some suggested solutions and current initiatives working towards improvements in these areas. Some examples of good practice in this field are also discussed.ConclusionsMany of the historical problems with surgical trial outcomes may be overcome with an increased understanding of the trial design and purpose and recognition that pragmatic trials require assessments of outcomes that are patient-centred in addition to measurement of short-term outcomes. The use of core outcome sets developed for specific surgical interventions and the application of novel methods to blind outcome assessors will also improve outcome measurement and reporting. It is recommended that surgeons work together with trial methodologists to integrate these approaches into RCTs in surgery. This will facilitate the appropriate evaluation of surgical interventions with informative outcomes so that results from trials can be useful for clinical practice.

What are the roles and valued attributes of a Trial Steering Committee? Ethnographic study of eight clinical trials facing challenges

BackgroundClinical trials oversight by a Trial Steering Committee (TSC) is mandated by Good Clinical Practice. This study used qualitative methods to explore the role and valued attributes of the TSC to inform planned updates of Medical Research Council guidance and TSC terms of reference.MethodsAn ethnographic study was conducted during 2013–2014. TSC and Trial Management Group meetings from eight trials were observed and audio-recorded, and semi-structured interviews conducted with purposively sampled key informants: independent and non-independent TSC members, trial sponsor representatives, funder representatives and chief investigators. The selected trials were currently recruiting and dealing with challenging scenarios. Data were analysed thematically and findings triangulated and integrated to give a multi-perspective account of the role and valued attributes of a TSC.ResultsEight TSC meetings and six Trial Management Group meetings were observed. Sixty-five interviews were conducted with 51 informants. The two main roles played by the TSC were quality assurance and patient advocacy. Quality assurance involved being a ‘critical friend’ or a provider of ‘tough love’. Factors influencing the ability of the TSC to fulfil this role included the TSC Chair, other independent TSC members and the model of the TSC and its fit with the trial subject. The role of the TSC as an advocate for patient well-being was perceived as paramount. Two attributes of TSC members emerged as critical: experience (of running a trial, trial oversight or in a clinical/methodological area) and independence. While independence was valued for giving impartiality, the lack of consensus about its definition and strict requirements of some funders made it difficult to operationalise.ConclusionsWe found tensions and ambiguities in the roles expected of TSCs and the attributes valued of TSC members. In particular, the requirements of independence and experience could conflict, impacting the TSCs’ quality assurance role. Concerns were raised regarding whose interests are served by funders’ criteria of independence; in particular, funders’ selection of TSC members was thought to potentially inhibit TSCs’ ability to fulfil their patient advocacy role. These findings should be incorporated in revising guidance and terms of reference for TSCs.